The Next Generation of Agents for Lung Cancer

At the 16th Annual International Lung Cancer Congress, Tony Mok, MD, Professor of Clinical Oncology at the Chinese University of Hong Kong, provided an overview of the next generation of agents, taking stock of the recent past for insights into the future of drug discovery.

Drug discovery is rarely, if ever, an overnight occurrence. Rather, as Dr Mok described it, the journey from data to practice is often decades in the making.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first generation of agents to show success in the management of lung cancer. These drugs, which block the signal from EGFR that tells cells to grow, can be used without chemotherapy as a first-line treatment for advanced non–small-cell lung cancers (NSCLCs) that have certain mutations in the EGFR gene.

First discovered in 1960 and sequenced in 1990, it was not until the recent discovery of EGFR mutations that these agents could yield response rates >70%.

From there, combination regimens have been developed to enrich and improve therapy, and these agents have since been extended to the adjuvant and stage III settings. If results of the ongoing ARCHER 1050 phase 3 study are positive, dacomitinib will become the fourth EGFR-TKI available for the first-line setting.

The list of anaplastic lymphoma kinase (ALK) inhibitors is not very long. Crizotinib is the current standard, but the ALEX Study, a randomized, phase 3 trial comparing alectinib with crizotinib in treatment-naïve patients with ALK-positive advanced NSCLC may soon change this paradigm. “The study is accruing quite well,” Dr Mok said. “Hopefully, within a year and a half we may be able to get some answers.”

Another study from the National Cancer Institute is comparing a number of different TKIs to determine the optimal sequence of ALK inhibitors, and raises additional questions for clinicians: “Is progression-free survival the best end point or is it overall survival,” Dr Mok asked the audience. “How do we develop rational combinations given the large number of bypass tracks that can mediate ALK TKI resistance? Given that 30% to 40% of ALK-positive patients may have brain metastases, how do we determine the most effective ALK inhibitors for penetration of the central nervous system?”

Although there are several ongoing studies testing numerous potential agents, Dr Mok put emphasis on entrectinib because it is one agent that could be beneficial for ROS1 and NTRK.

A basket study—a new form of clinical trial design that explores responses to drugs based on the specific mutations in patients’ tumors rather than where their cancer originated—is also under way. The STARTRK-2 study will test entrectinib in patients with NSCLC, colorectal cancer (CRC), and non-NSCLC/non-CRC solid tumors. As long as patients are ROS1 positive, they can receive the drug, according to Dr Mok. “We are transitioning from tissue-based to molecule-based therapy,” he added.

Finally, another gene that shows promise but has not been investigated is TUSC2. Data have been interesting thus far, he said. Despite these exciting developments, Dr Mok concluded his talk with a reminder of an area in which lung cancer therapy may lag behind the rest of oncology.

“Epigenetics has been around for over a decade,” he said, “and a number of therapies have been approved for hematologic disorders, so it is possible that epigenetics can make a difference in cancer management.” For lung cancer, however, the response rate is between 0% and 2%.